One general method of preparing ceftazidime which is disclosed in U.S. Pat. No. 4,258,041 involves a series of reactions to form the side-chain acid of ceftazidime or a reactive derivative thereof followed by coupling with the 7-.beta.-amino cephalosporin nucleus. Two of the intermediates described in such a series of reactions for the preparation of a protected form of the 7-side chain are (Z)-2-(2-tert. -butoxycarbonylprop-2-oxyimino)-2-(2-triphenylmethylaminothiazol-4-yl) acetic acid and its ethyl ester. However, these intermediates suffer from a number of disadvantages on a manufacturing scale. This material has a variable form which changes on mechanical handling, thus making it difficult to filter satisfactorily.
To overcome the problems faced at a manufacturing scale, an improved form of the intermediate was prepared, such as crystalline (Z)-2-(2-tert. -butoxycarbonylprop-2-oxyimino)-2-(2-triphenylmethylaminothiazol-4-yl)acet ic acid associated with 0.1 to 0.6 moles of dioxan per mole of acid. This process is disclosed in U.S. Pat. No. 4,493,933. In U.S. Pat. No. 4,665,167, a crystalline (Z)-2-(2-tert. -butoxycarbonylprop-2-oxyimino)-2-(2-triphenylmethylarinothiazol-4-yl)acet ic acid is claimed which contains from 0.8 to 1.8 moles of methanol per mole of acid. The dioxan and methanol-associated acid also suffers from certain disadvantages on a commercial scale. Dioxan and methanol are highly flammable solvents and difficult to handle on a manufacturing scale.
The known methods in the literature for the preparation of (Z)-2-(2-tert.- butoxycarbonylprop-2-oxyimino)-2-(2-triphenylmethylaminothiazol-4-yl)aceti c acid (IV) involves the selective hydrolysis of Ethyl (Z)-2-(2-tert. -butoxycarbonylprop-2-oxyimino)-2-(2-triphenylmethylaminothiazol-4-yl)acet ate of Formula (VI) (Scheme II). ##STR3##
These methods give (Z)-2-(2-carboxylprop-2-oxyimino)-2-(2-triphenylmethylaminothiazol-4-yl) acetic acid as a side product, which is difficult to remove. Removal of this impurity is possible only by repeated crystallizations at the cost of the yield.